Evaluation of Cabozantinib in Radioiodine-Refractory Differentiated Thyroid Cancer Post-VEGFR-Targeted Therapy: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2024-516478-31-00
- Protocol
- XL184–311
- Sponsor
- Exelixis Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of **cabozantinib** compared with placebo on **Progression Free Survival (PFS)** and **Objective Response Rate (ORR)** in subjects with radioiodine-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy. This objective is clinically relevant as it aims to determine the efficacy of cabozantinib in prolonging the time patients live without disease progression and in improving the rate of tumor response, which are critical endpoints in the management of advanced thyroid cancer. No secondary objectives are specified for this study.
Participants
The clinical trial involves a total of **191 participants** diagnosed with **progressed thyroid cancer**, specifically focusing on those with Radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy. The study population includes both male and female subjects, with an age range starting from 16 years and above. Participants were selected based on their confirmed diagnosis of DTC and their previous treatment history with VEGFR-targeting TKI agents such as lenvatinib or sorafenib. The trial includes individuals who are capable of understanding and complying with the protocol requirements. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population also includes vulnerable groups, ensuring comprehensive representation. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific medical and hormonal therapy requirements, including thyroxine suppression therapy. The selection criteria ensure that participants have adequate organ and marrow function, as well as measurable disease according to RECIST 1.1 criteria. The sponsor has not provided additional information regarding specific lifestyle factors or habits of the participants.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **cabozantinib** in subjects with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy. The primary objective is to assess the effect of cabozantinib compared to placebo on progression-free survival (PFS) and objective response rate (ORR). The trial is expected to conclude by December 31, 2025, with recruitment having commenced on October 1, 2018. Participants will be randomly assigned to receive either cabozantinib or a placebo, with the study drug administered orally in the form of film-coated tablets.
The trial involves a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a histologically or cytologically confirmed diagnosis of differentiated thyroid cancer and prior treatment with VEGFR-targeting agents. Participants must also demonstrate adequate organ and marrow function and be capable of complying with protocol requirements. Following the screening, participants will undergo regular follow-up visits to monitor their response to treatment and assess any adverse events. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement is up to 51 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will measure primary endpoints such as PFS and ORR, with secondary endpoints including overall survival, duration of objective tumor response, safety and tolerability, and pharmacokinetics of cabozantinib. Additionally, the study will explore the relationship between biomarkers and clinical outcomes, as well as changes in health-related quality of life.
Treatment
The clinical trial involves the administration of **CABOMETYX** film-coated tablets, which contain the active substance **cabozantinib**. Two dosages are utilized: 60 mg and 20 mg. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose is 60 mg, with a total maximum dose of 91800 mg over a treatment period of up to 51 weeks. The tablets are manufactured by IPSEN PHARMA and are of chemical origin. The clinical trial material differs slightly from the investigational medicinal product (IMP) in relation to its marketing authorization. For further details, reference to the full Investigational Medicinal Product Dossier (IMPD) for cabozantinib is advised.
A **placebo** is also used in this study, which is matched to the cabozantinib investigational medicinal product (IMP) but does not contain the active substance. The placebo is identical in appearance to the active treatment to maintain the double-blind nature of the trial. The placebo is administered orally, following the same schedule as the active treatment, to ensure consistency in the administration process.
Efficacy
The efficacy of cabozantinib in the treatment of **radioiodine-refractory differentiated thyroid cancer** will be assessed through several primary and secondary endpoints. The primary endpoints include **Progression-Free Survival (PFS)** and **Objective Response Rate (ORR)**, both evaluated per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by a blinded independent radiology committee (BIRC). These endpoints will provide critical insights into the drug's effectiveness in delaying disease progression and achieving tumor response.
Secondary endpoints will further explore the drug's impact on **Overall Survival (OS)**, the **Duration of Objective Tumor Response**, and the **Safety and Tolerability** of the treatment. Additionally, the pharmacokinetics (PK) of cabozantinib will be analyzed to understand its absorption, distribution, metabolism, and excretion. The study will also investigate the relationship between baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), circulating tumor cells (CTCs), and circulating DNA (ctDNA) with treatment outcomes. Patient-reported outcomes will be assessed using the EuroQol Health questionnaire instrument (EQ-5D-5L) to evaluate changes in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health. Health care resource utilization will also be monitored as part of the secondary endpoints.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Histologically or cytologically confirmed diagnosis of DTC, including the following subtypes (Note: results of a previous biopsy will be accepted): a. PTC including histological variants of PTC such as follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, arthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and poorly differentiated
- Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to randomization
- Must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC
- Must have been previously treated with at least one of the following VEGFR-targeting TKI agents for DTC: lenvatinib or sorafenib. (Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited to) lenvatinib and sorafenib.)
- Must have experienced documented radiographic progression per RECIST 1.1 per Investigator during or following treatment with a VEGFRtargeting TKI prior to starting the next anticancer therapy (which may be treatment in this study)
- Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
- Age ≥ 16 years old on the day of consent
- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
- Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before randomization:a. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without receipt of granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN if the subject has documented bone metastases e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert's disease ≤ 3 × ULN f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula). g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
- Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff of the reference range or less than 0.50 mIU/L (<0.50 μIU/mL), whichever is lower, within 28 days before randomization. (Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be targeted.)
- Capable of understanding and complying with the protocol requirements and signed informed consent (or informed assent and parental/guardian consent for subjects < 18 years of age)
- Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 4 months after the last dose of study treatment. For females, such methods include combined hormonal contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable hormonal contraception), placement of an intrauterine device, or placement of an intrauterine hormone-releasing system. Males must agree to use a barrier method (eg, condom) unless they have had a vasectomy.
- Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 45 years-of-age in the absence of other biological or physiological causes. In addition, females under 55 yearsof-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.
Exclusion Criteria
- Prior treatment with any of the following: a. Cabozantinib b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib) c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib, pazopanib, axitinib, vandetanib) d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent) e. More than 1 systemic chemotherapy regimen (given as single agent or in combination with another chemotherapy agent)
- Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before randomization
- Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
- Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not eligible (eg, radiation esophagitis or other inflammation of the viscera).
- Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before randomization. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
- Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed anticoagulants: • Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH) • Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before randomization and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
- The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: a. Cardiovascular disorders: i. Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, serious cardiac arrhythmias ii. Uncontrolled hypertension defined as sustained blood pressure (BP) >150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], pulmonary embolism) within 6 months before randomization. Subjects with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before randomization. b. Gastrointestinal disorders (GI; eg, malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation: i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (>2.5 mL) of red blood or history of other significant bleeding within 3 months before randomization d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation e. Lesions invading major pulmonary blood vessels f. Other clinically significant disorders such a: • Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection• Serious non-healing wound/ulcer/bone fracture • Malabsorption syndrome • Moderate to severe hepatic impairment (Child-Pugh B or C) • Requirement for hemodialysis or peritoneal dialysis • Uncontrolled diabetes mellitus • History of solid organ transplantation
- Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before randomization. Complete wound healing from major surgery must have occurred 4 weeks before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. For further exclusion criteria, please, see protocol section 4.3
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 01 Oct 2018 | 2 |
 Romania | Not Recruiting | 01 Oct 2018 | 1 |
 Spain | Not Recruiting | 01 Oct 2018 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CABOMETYX 60 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 60 | 51 | PRD4382746 |
Cabozantinib-matched placebo identical to the IMP apart from the active substance | Placebo | N/A | — | — | — | N/A |
CABOMETYX 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 60 | 51 | PRD4381882 |